1. Technical Field of the Invention
The present invention generally relates to compositions and methods for prevention of proliferative disorders, including restenosis, atherosclerosis and cancer. More particularly, the invention relates to compositions containing molecules secreted by cells and which are capable of inhibiting proliferation of those and/or other cells. The invention also relates to therapeutic methods employing such compositions.
2. Description of Related Art
Percutaneous transluminal coronary interventions (“PCI”) such as angioplasty procedures are common practice today for relieving atherosclerotic blockage caused by fatty acid deposits in coronary arteries, whereby blood flow is restored in the affected arteries. A relatively common complication of angioplasty is restenosis, a renarrowing of the blood flow due to uncontrolled proliferation of smooth muscle cells at the angioplasty site. Post-angioplasty restenosis was first treated by balloon redilatation and, when stents became available1, by stent implantation2. However, close to 20% of patients developed restenosis within the stent (“in-stent restenosis”)2, due to neointimal VSMC growth3. In-stent restenosis was initially treated by repeat angioplasty, rotational atherectomy, laser angioplasty, “stent-in-stent”, and other techniques, but all of those procedures yielded suboptimal outcomes4. Brachytherapy has been investigated for preventing restenosis12,13 after primary angioplasty, however, at least 15% of patients treated with brachytherapy still develop restenosis, suggesting that the prevention of restenosis by brachytherapy is not entirely efficacious13. It has been reported that brachytherapy only moderately reduced the recurrence rate of in-stent restenosis (from 43.8% to 28.2%)5, at the expense of adverse radiation exposure both to patients and operators and of late-occurring, intralesional thrombosis.
Among a number of pharmacological interventions attempted, only a few preventive strategies, such as probucol6, trapidil7, cilostazol8, n-3 fatty acid (eicosapentaenoic acid)9, and folic acid combined with vitamin B12 and pyridoxine10, have been found acceptable. Even in the better trials, restenosis still developed in 17.9–24.2% of patients. When stent implantation was used to treat primary lesions in order to prevent restenosis, a significant number (18%) of patients who underwent stent implantation experienced restenosis nevertheless1,2,11. It has been reported that stents coated with sirolimus (also known as rapamycin) are more effective than conventional stents in a randomized, double-blind clinical trial55, and recently the FDA has approved a sirolimus-eluting coronary stent for angioplasty procedures to open clogged coronary arteries. Long-term effects and side-effect profiles of sirolimus have not been determined in a large clinical trail, however.
Although brachytherapy and sirolimus-eluting stents may effectively treat a selected group of patients with restenosis, those treatment modalities are likely to remain very expensive and exclusive. For example, the cost of sirolimus-eluting stents is estimated to be four times higher than that of conventional stents, while brachytherapy requires the involvement of radiation oncologists and nuclear physicists. It has been estimated that up to a million PCIs are being performed annually in North America alone14. A therapeutically viable, lower-cost treatment that can significantly reduce the risk of restenosis is greatly needed. It has been calculated that a treatment that reduces risk of restenosis by 25–33% risk reduction would save approximately $1,400–$2,000 per patient in hospital, procedural and professional fees, with a total savings in North America alone of $400–800 million a year15.